Mood disorders are a group of severe mental Illnesses that directly affect over 20% of individuals in the U.S. Since neurobiology of mood disorders is not fully understood, the diagnosis is lack of neurobiological basis and the treatment options are still limited. Based on the accumulating evidence that glycogen synthase kinase-3 (GSK3) plays a major role in the neuropathology and treatment of mood disorders, in our ongoing ROl research project, we are studying regulation of GSK3 In animal brain by several pharmacological treatments used in mood disorders. Our new findings suggest that anticonvulsant mood stabilizers, monoamine modulating antidepressants, and dual-acting antipsychotics all inactivate GSK3 by increasing its inhibitory N-terminal serine phosphorylation, a mechanism known to be regulated by the mood stabilizer lithium and brain-derived neurotrophic factor (BDNF). We therefore further hypothesize that regulation of the inhibitory serine phosphorylation of GSK3 has a fundamental impact in the stability of mood-relevant behaviors and pharmacotherapy of mood disorders. In this new K02 proposal, we will test this hypothesis in genetically engineered mice that carry GSK3 with a dual alanine mutation at the serine-21 of GSKSa and serine-9 of GSK3P (referred as GSK3 knock-in mice). First, we will test depressive-like and manic-like behaviors in GSK3 knock-in and matching wild type mice. This will be followed by comparing the behavioral responses of GSK3 knock-in and matching wild type mice to pharmacological agents used in mood disorders. The significance of this study is to evaluate the behavioral impact of a post-translational modification of GSK3 and its potential as a new drug target in the treatment of mood disorders. Since studying animal behaviors using genetically modified animal models is not a specialty of the principal investigator, the application is submitted as a career development project, in which the candidate of this application will use protected research time to learn new techniques, obtain hands-on experience, and gain new knowledge in developing genetically modified animals, designing and performing behavior experiments, and conducting comprehensive statistical analysis. Learning experience and research findings obtained from this career enrichment project will have significant implications in the candidate's future research, which is envisioned as gaining expertise in using animal models to study neuropathology of mood disorders and translating biological findings from animal models to findings in mood disorder patients. PUBLIC HEALTH RELEVANCE: This K02 project, by establishing an animal model and utilizing the model to examine the therapeutic mechanisms of mood disorders, will provide the applicant with a career development opportunity to work toward increasing our understanding of the neuropathology and treatment of mood disorders, therefore will have a direct impact in improving our care to over 20% population affected by mood disorders.